Diverse
classes of natural products contain chiral 1,5-polyols,
within which may be stereochemical triads of 1,5,9- and 1,5,7-triols.
Biological activities associated with compounds containing these motifs
warrant targeted synthetic strategies to access all stereoisomers
of a 1,5-polyol family from cheap and easily accessible reagents while
avoiding the need to determine configurations at each alcohol stereocenter.
Here, we address these problems via design and implementation of an
iterative configuration-encoded strategy to access 1,5-polyols with
unambiguous stereocontrol; the coupling event exploits Julia–Kocienski
reactions of enantiopure α-silyloxy-γ-sulfononitriles.
These building blocks, bearing sulfone at one terminus and α-silyloxyaldehyde
(in latent form) at the other, were prepared via asymmetric catalysis.
An efficient scalable route to these building blocks was developed,
leading to enantiopure samples in multigram quantities. Preliminary
studies of acetals as the latent aldehyde functionality in the α-silyloxyaldehyde
showed that Julia–Kocienski coupling of these building blocks
was effective, but iterative application was thwarted during acetal
hydrolysis, leading to use of nitrile to perform the latent aldehyde
function. A variety of 1,5-polyols, including a 1,5,9,13-tetraol and
a differentially protected 1,5,9-triol, were prepared, validating
the approach. The accompanying paper describes the application of
this configuration-encoded 1,5-polyol synthesis to 1,5,9- and 1,5,7-triols
found in tetrafibricin.
